The various forms of asbestos, among which are chrysotile, crocidolite and amosite, have been found to be toxic toward mammals, particularly when inhaled. They typically produce inflammation, fibrous scarring and cancer. While it appears that the size of asbestos fibers are important in determining the amount of toxicity produced, the nature of the chemical interaction between asbestos and cells is also important.
One feature of the response to inhalation of asbestos fibers is the fiber attachment to and/or engulfment by phagocytic cells (the pulmonary macrophages) and subsequent inflammation. The inflammatory phagocytes reduce oxygen to reactive metabolites, such as the superoxide anion radical, hydrogen peroxide and the hydroxyl radical. The hydroxyl radical is a potent oxidizing agent which initiates lipid peroxidation, kills bacteria, damages cellular DNA, and reacts with most organic molecules. This radical is ordinarily generated by stimulated phagocytes in concentrations much lower that those of the other, more stable, reduced oxygen species: superoxide and hydrogen peroxide. While these latter species may be produced by direct enzymatic reduction of oxygen, it is believed that under physiological conditions, generation of hydroxyl radicals is a secondary process catalyzed by metals, such as iron or copper.
It has been proposed to treat asbestos with various metal salts, including iron salts, to reduce its biologically harmful properties by way of metal-micelle formation. U.S. Pat. No. 4,328,197. The chelating agent disodium ethylenediamine tetraacetic acid (EDTA) has also been reacted with asbestos and shown to be less harmful to living cells. U.S. Pat. Nos. 4,168,346, 4,234,377 and 4,309,477. However, EDTA has been shown to enhance rather than inhibit the peroxide catalytic activity of asbestos. Weitzman, S. A. and P. Graceffa, Arch. Biochem. Biophys. 220:373-376 (1984).
Asbestos contains iron as part of its crystalline structure and/or as a contaminant. The presence of iron in asbestos has been shown to catalyze hydroxyl and superoxide radical generation from hydrogen peroxide which is a normal by-product of tissue metabolism. Weitzman, S. A. and P. Graceffa, Arch. Biochem. Biophys. 228:373-376 (1984). They found that a hydroxamic acid iron chelating agent, desferroxamine, could complex the asbestos iron and inhibit its ability to produce hydroxyl radicals. Toxicity of asbestos can be inhibited or reduced by treating asbestos with other non-mutagenic non-toxic hydroxamic acid iron chelating agents, such as desferrichromes, fusarinines, myobactin P., mycchanamide, hadacidin, aspergillic acid, pulcherriminic acid, rhodotarulic acids, and citrate-hydroxaminic acids, and salts thereof. Graceffa, P. and S. A. Weitzman, U.S. Pat. No. 4,474,742, issued Oct. 2, 1984.
Nonfibrous silicates have also been shown to produce toxic hydroxyl radicals in the lung by a mechanism similar to asbestos. Kennedy T. P. et al., Arch. Biochem. Biophys., 269:359-364 (1989); Gulumian M. and J. A. Van Wyk, Chem.-Biol. Interactions 62:89-97 (1987).
Although hydroxyl radical production can be inhibited by such treatment, the cost of desferroxamine is prohibitively high for the large amount of asbestos that requires treatment. Thus, it would be desirable to provide a method for inhibiting peroxide-reduction catalytic activity of asbestos using an iron complexing agent which is abundant, relatively inexpensive and nontoxic.